Helbig, Ingo3; Swinkels, Marielle E M4; Aten, Emmelien5; Caliebe, Almuth6; van 't Slot, Ruben4; Boor, Rainer3; von Spiczak, Sarah3; Muhle, Hiltrud3; Jähn, Johanna A3; van Binsbergen, Ellen4; van Nieuwenhuizen, Onno7; Jansen, Floor E7; Braun, Kees P J7; de Haan, Gerrit-Jan8; Tommerup, Niels11; Stephani, Ulrich3; Hjalgrim, Helle10; Poot, Martin4; Lindhout, Dick4; Brilstra, Eva H4; Møller, Rikke S12; Koeleman, Bobby P C4
1 Section IV. Building 22.4/24.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Medical Genetics Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.4 Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht5 Department of Medical Genetics, Leiden University Medical Center, Leiden, The Netherlands.6 Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.7 Department of Child Neurology, Rudolf Magnus Institute of Neurosciences, University Medical Center Utrecht, The Netherlands.8 SEIN Epilepsy Institute in the Netherlands Foundation, Hoofddorp, The Netherlands.9 Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet10 Danish Epilepsy Centre, Dianalund, Kolonivej 7, 4293, Dianalund, Denmark, firstname.lastname@example.org Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet12 Section IV. Building 22.4/24.4, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.
European Journal of Human Genetics, 2014, Vol 22, Issue 7, p. 896-901